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P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7)

Identity

Other namesMGC20089
P2X7
P2Z
HGNC (Hugo) P2RX7
LocusID (NCBI) 5027
Location 12q24.31
Location_base_pair Starts at 121570631 and ends at 121624354 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The P2RX7 gene is comprised of 13 coding exons.
Transcription The full length transcript is 3135 bp long and 10 alternative splicing isoforms have been identified.
Pseudogene Not known.

Protein

Description The protein has 595 residues amino acids and compromises a 69 kDa calculated molecular weight. However, N-glycosylation in the extracellular loop increases the size of the P2X7 receptor to about 75-85 KDa; the protein is composed successively (from the N- to the C-terminus) by:
  • 25 amino acid intracellular N-terminus
  • 21 amino acid first transmembrane domain
  • 288 amino acid extracellular loop
  • 21 amino acid second transmembrane domain
  • 240 amino acid intracellular C-terminal region
    • Expression In a wide variety of tissues including heart, liver, pancreas, thymus, skeletal muscle and brain, although in brain the expression is mainly restricted to microglia. It also has relevant expression and function in immune cells (mainly in antigen presenting cells, such as monocytes, macrophages and dendritic cells).
    Localisation Mainly is found in the plasma membrane, however it also can be found in intracellular membrane compartments while trafficking to the plasma membrane.
    Function Acts as a ligand gated ion channel, sensing high concentration of extracellular ATP. Responsible for ATP-dependent activation and release of proinflammatory cytokines of the interleukin-1 family, mainly interleukin-1beta, interleukin-18 and interleukin-1alpha, playing a pivotal role in inflammatory responses. Prolonged stimulation of the P2X7 receptor can lead to plasma membrane bleb formation, opening of pannexin-1 dependent membrane pores and eventual cell death.
    Homology With other P2X receptors, with the higher homology with P2RX4. Excluding the unique C-terminal domain, homology is 39-49% with other P2X receptors.

    Mutations

    Germinal The human P2X7 receptor gene is highly polymorphic and more then 260 SNP have been described, only four loss-of-function and one gain-of-function SNP have been described to date:
  • Loss of protein function:
    946 G to A (Arg-307 to Gln)
    1068 G to A (Ala-348 to Thr)
    1513 A to C (Glu-496 to Ala)
    1729 T to A (Ile-568 to Asp)
  • Gain of protein function:
    489 C to T (His-155 to Tyr)
    • Somatic Not known in human.

    Implicated in

    Entity Extrapulmonary tuberculosis
    Note The P2RX7 1513C allele has been strongly associated with extrapulmonary tuberculosis. The allele was associated with a reduced killing of Mycobacterium tuberculosis by macrophages.
      
    Entity Chronic lymphoid leukemia (CLL)
    Note The 1513C allele of P2RX7 has been associated with the clinical course of patients affected by chronic lymphocytic leukemia (CLL).
    There is a possible role for the P2X7 receptor in the susceptibility to familial CLL or, alternately, the 1513C allele may be in linkage disequilibrium with a nearby susceptibility gene.
      
    Entity Various cancers, including breast cancer, prostate cancer, papillary thyroid cancer and neuroblastoma.
    Note P2X7 receptor is overexpressed in a variety of cancers (see above). A detailed understanding of the mechanistic contribution mediated by P2RX7 has yet to be established. However, there is substantial evidence that the P2X7 receptor may mediate cell survival and growth by increasing the efficiency of oxidative phosphorylation and total intracellular ATP stores. Finally it has been proposed that the P2X7 receptor may be a candidate marker of papillary thyroid cancer.
      

    External links

    Nomenclature
    HGNC (Hugo)P2RX7   8537
    Entrez_Gene (NCBI)P2RX7  5027  purinergic receptor P2X, ligand-gated ion channel, 7
    Cards
    AtlasP2RX7ID41623ch12q24
    GeneCards (Weizmann)P2RX7
    Ensembl (Hinxton)ENSG00000089041 [Gene_View]  chr12:121570631-121624354 [Contig_View]  P2RX7 [Vega]
    AceView (NCBI)P2RX7
    Genatlas (Paris)P2RX7
    euGene (Indiana)5027
    SOURCE (Stanford)NM_002562 NM_177427
    Genomic and cartography
    GoldenPath (UCSC)P2RX7  -  12q24.31   chr12:121570631-121624354 +  12q24   [Description]    (hg19-Feb_2009)
    EnsemblP2RX7 - 12q24 [CytoView]
    Mapping of homologs : NCBIP2RX7 [Mapview]
    OMIM151400   602566   
    Gene and transcription
    Genbank (Entrez)AB209709 AK090866 AK225163 AK290405 AK294126
    RefSeq transcript (SRS)NM_002562 NM_177427
    RefSeq transcript (Entrez)NM_002562 NM_177427
    RefSeq genomic (SRS)AC_000144 NC_000012 NG_011471 NT_009775 NW_001838063
    RefSeq genomic (Entrez)AC_000144 NC_000012 NG_011471 NT_009775 NW_001838063
    Consensus coding sequences : CCDS (NCBI)P2RX7
    Cluster EST : UnigeneHs.729169 [ SRS ] Hs.729169 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)14226
    Alternative Splicing GalleryENSG00000089041
    Gene ExpressionP2RX7 [ NCBI-GEO ]   P2RX7 [ EBI - ARRAY_EXPRESS ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ99572 (SRS) Q99572 (Uniprot)
    With graphics : InterProQ99572
    Splice isoforms : SwissVarQ99572(Swissvar)
    Domaine pattern : Prosite (SRS)P2X_RECEPTOR (PS01212)   
    Domaine pattern : Prosite (Expaxy)P2X_RECEPTOR (PS01212)   
    Domains : Interpro (SRS)P2X7_purnocptor    P2X_purnocptor   
    Domains : Interpro (EBI)P2X7_purnocptor    P2X_purnocptor   
    Related proteins : CluSTrQ99572
    Domain families : Pfam (SRS)P2X_receptor (PF00864)   
    Domain families : Pfam (Sanger)P2X_receptor (PF00864)   
    Domain families : Pfam (NCBI)pfam00864   
    Blocks (Seattle)Q99572
    Human Protein AtlasENSG00000089041
    HPRD03977
    IPIIPI00293328   IPI01010105   IPI01012970   IPI00396134   IPI01019121   IPI01010340   IPI01010806   IPI00654863   IPI01014845   IPI01015465   IPI01014429   IPI00377108   
    Protein Interaction databases
    DIP (DOE-UCLA)Q99572
    IntAct (EBI)Q99572
    FunCoupENSG00000089041
    REACTOMEP2RX7
    BioGRIDP2RX7
    InParanoidQ99572
    Interologous Interaction database Q99572
    Polymorphism : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)P2RX7
    SNP (GeneSNP Utah)P2RX7
    SNP : HGBaseP2RX7
    Genetic variants : HAPMAPP2RX7
    Somatic Mutations in Cancer : COSMICP2RX7 
    CONAN: Copy Number AnalysisP2RX7 
    Mutations and Diseases : HGMDP2RX7
    OMIM151400    602566   
    GENETests151400    602566   
    Disease Genetic AssociationP2RX7
    Huge Navigator P2RX7 [HugePedia]  P2RX7 [HugeCancerGEM]
    Genomic VariantsP2RX7
    snp3D : Map Gene to Disease5027
    General knowledge
    Homologs : HomoloGeneP2RX7
    Homology/Alignments : Family Browser (UCSC)P2RX7
    Phylogenetic Trees/Animal Genes : TreeFamP2RX7
    Chemical/Protein Interactions : CTD5027
    Chemical/Pharm GKB GenePA32866
    Clinical trialP2RX7
    Cancer Resource (Charite)ENSG00000089041
    Ontology : AmiGOlipopolysaccharide binding  purinergic nucleotide receptor activity  regulation of sodium ion transport  receptor activity  extracellular ATP-gated cation channel activity  receptor binding  ion channel activity  ATP binding  ATP binding  cytoplasm  plasma membrane  plasma membrane  integral to plasma membrane  ion transport  cell surface receptor signaling pathway  positive regulation of calcium ion transport into cytosol  membrane  membrane  sensory perception of pain  positive regulation of bone mineralization  bleb  bleb assembly  response to ATP  purinergic nucleotide receptor signaling pathway  nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway  protein homodimerization activity  regulation of apoptotic process  negative regulation of MAPK cascade  innate immune response  negative regulation of bone resorption  positive regulation of cytolysis  pore complex assembly  positive regulation of interleukin-1 beta secretion  positive regulation of cytoskeleton organization  regulation of killing of cells of other organism  membrane depolarization  
    Ontology : EGO-EBIlipopolysaccharide binding  purinergic nucleotide receptor activity  regulation of sodium ion transport  receptor activity  extracellular ATP-gated cation channel activity  receptor binding  ion channel activity  ATP binding  ATP binding  cytoplasm  plasma membrane  plasma membrane  integral to plasma membrane  ion transport  cell surface receptor signaling pathway  positive regulation of calcium ion transport into cytosol  membrane  membrane  sensory perception of pain  positive regulation of bone mineralization  bleb  bleb assembly  response to ATP  purinergic nucleotide receptor signaling pathway  nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway  protein homodimerization activity  regulation of apoptotic process  negative regulation of MAPK cascade  innate immune response  negative regulation of bone resorption  positive regulation of cytolysis  pore complex assembly  positive regulation of interleukin-1 beta secretion  positive regulation of cytoskeleton organization  regulation of killing of cells of other organism  membrane depolarization  
    Pathways : KEGGCalcium signaling pathwayNeuroactive ligand-receptor interaction
    Other databases
    Probes
    Probes : ImagenesP2RX7 Related clones (RZPD - Berlin)
    Litterature
    PubMed187 Pubmed reference(s) in Entrez
    PubGeneP2RX7
    iHOPP2RX7

    Bibliography

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    Science (New York, N.Y.). 1996 ; 272 (5262) : 735-738.
    PMID 8614837
     
    The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA.
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    The Journal of biological chemistry. 1997 ; 272 (9) : 5482-5486.
    PMID 9038151
     
    A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.
    Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS
    The Journal of biological chemistry. 2001 ; 276 (14) : 11135-11142.
    PMID 11150303
     
    P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia.
    Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR
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    Molecular physiology of P2X receptors.
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    PMID 12270951
     
    An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor.
    Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R
    The Journal of biological chemistry. 2003 ; 278 (19) : 17108-17113.
    PMID 12586825
     
    Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia.
    Dao-Ung LP, Fuller SJ, Sluyter R, SkarRatt KK, Thunberg U, Tobin G, Byth K, Ban M, Rosenquist R, Stewart GJ, Wiley JS
    British journal of haematology. 2004 ; 125 (6) : 815-817.
    PMID 15180873
     
    An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor.
    Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS
    The Journal of biological chemistry. 2004 ; 279 (30) : 31287-31295.
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    Differentiation between cancerous and normal hyperplastic lobules in breast lesions.
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    Breast cancer research and treatment. 2004 ; 83 (1) : 1-10.
    PMID 14997049
     
    Differentiation between cancerous and normal hyperplastic lobules in breast lesions.
    Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird A, Barden JA
    Breast cancer research and treatment. 2004 ; 83 (1) : 1-10.
    PMID 14997049
     
    Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth.
    Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F
    Molecular biology of the cell. 2005 ; 16 (7) : 3260-3272.
    PMID 15901833
     
    A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes.
    Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F
    Journal of immunology (Baltimore, Md. : 1950). 2005 ; 175 (1) : 82-89.
    PMID 15972634
     
    Identification and characterization of splice variants of the human P2X7 ATP channel.
    Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S
    Biochemical and biophysical research communications. 2005 ; 332 (1) : 17-27.
    PMID 15896293
     
    A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization.
    Feng YH, Li X, Wang L, Zhou L, Gorodeski GI
    The Journal of biological chemistry. 2006 ; 281 (25) : 17228-17237.
    PMID 16624800
     
    The P2X7 receptor: a key player in IL-1 processing and release.
    Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F
    Journal of immunology (Baltimore, Md. : 1950). 2006 ; 176 (7) : 3877-3883.
    PMID 16547218
     
    Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.
    Pelegrin P, Surprenant A
    The EMBO journal. 2006 ; 25 (21) : 5071-5082.
    PMID 17036048
     
    The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism.
    Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V
    Cancer research. 2006 ; 66 (2) : 907-914.
    PMID 16424024
     
    A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.
    Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB, Wiley JS, Britton WJ
    American journal of respiratory and critical care medicine. 2007 ; 175 (4) : 360-366.
    PMID 17095747
     
    Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease?
    Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG, Dardano A, Faviana P, Madec S, Di Virgilio F, Monzani F
    Endocrinology. 2008 ; 149 (1) : 389-396.
    PMID 17947359
     
    REVIEW articlesautomatic search in PubMed
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    Contributor(s)

    Written01-2008Pablo Pelegrin, Annmarie Surprenant
    Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK

    Citation

    This paper should be referenced as such :
    Pelegrin P, Surprenant A . P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7). Atlas Genet Cytogenet Oncol Haematol. January 2008 .
    URL : http://AtlasGeneticsOncology.org/Genes/P2RX7ID41623ch12q24.html

    This paper is referenced by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/38574/1/01-2008-P2RX7ID41623ch12q24.pdf   [ Bibliographic record ]

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